川芎嗪中间体2-氯甲基-3,5,6三甲基吡嗪的合成优化  

Synthesis optimization of 2-chloromethyl-3,5,6-trimethylpyrazine derivative as the intermediate of ligustrazine

作　　者：赵蕊 张欣钰 吴高荣 徐冰[1] 韩耀天 陈萌 王鹏龙[1] 雷海民[1] ZHAO Rui;ZHANG Xinyu;WU Gaorong;XU Bing;HAN Yaotian;CHEN Meng;WANG Penglong ＊;LEI Haimin ＊(School of Chinese Pharmacy,Beijing University of Chinese Medicine,Beijing 102488,China)

机构地区：[1]北京中医药大学中药学院,北京102488

出　　处：《西北药学杂志》2018年第3期380-384,共5页Northwest Pharmaceutical Journal

基　　金：国家自然科学基金项目(编号:81173519);北京市中药基础与新药研究重点实验室共建项目(编号:1000062520493);北京中医药大学创新团队资助项目(编号:2011-CXTD-15)

摘　　要：目的对比"一步法"与"四步法"的制备方法,同时对"四步法"的关键步骤进行探讨,确定并优化川芎嗪中间体2-氯甲基-3,5,6三甲基吡嗪(TMP-Cl)的合成方法。方法分别通过自由基卤代的"一步法"以及氧代、乙酰化、水解和温和卤代的"四步法"合成TMP-Cl,结合HPLC监测反应进程,并借助HRMS、1 H-NMR和13 C-NMR确认化合物结构。结果本实验"四步法"中首次采用未见报道的TsCl/TEA/DMAP体系进行温和卤代反应,单步产率近100%。综合对比研究发现,"四步法"副产物少且反应条件温和,终产物产率高达80%。而"一步法"反应剧烈,副产物较多,主产物产率在50%左右。结论 "四步法"反应条件温和、刺激性小、产率高、后处理简单,是TMP-Cl的最佳合成方法,对于川芎嗪衍生物的后期设计、合成具有实际参考意义。Objective To compare the synthesis methods of＂one-step method＂ and＂four-step method＂ and explore the key steps of the＂four-step method＂,and finally to determine and optimize the synthesis method of the key intermediate of ligustrazine,2-chloromethyl-3,5,6-trimethylpyrazine（TMP-Cl）.Methods TMP-Cl was synthesized by free radical halogenation＂ one-step process＂and oxygen generation,acetylation,hydrolysis,mild halogenation＂four-step process＂,combined with HPLC to monitor the reaction process,and HRMS,1 H-NMR and 13 C-NMR were used to confirm the structure of compounds.Results The mild halogenation＂ reaction was firstly carried out in the＂four-step method＂ with TsCl/TEA/DMAP system which had never been reported yet.And the single-step yield was nearly 100%.After comparison,we found that the＂four-step method＂ shared the merits of less by-products and mild reaction conditions.The final product yield was as high as 80%.The＂one-step method＂ was harsh in condition to produce much more by-products than the＂ four-step method＂.The main product yield of＂ one-step method＂ was about50%.Conclusion The ＂four-step method＂has the advantages of mild reaction conditions,small stimulus,high yield and simple post-treatment.It is the satisfactory method for the synthesis of TMP-Cl,which could provide a practical reference for the future designing and synthesizing the ligustrazine derivatives.

关 键 词：2-氯甲基-3 5 6-三甲基吡嗪 一步法 四步法 温和卤代 

分 类 号：R914[医药卫生—药物化学]